Development of cebranopadol, a potent dual MOP/NOP agonist, for the treatment of Opioid Use Disorder (OUD)

开发cebranopadol,一种有效的双重MOP/NOP激动剂,用于治疗阿片类药物使用障碍(OUD)

基本信息

  • 批准号:
    10759100
  • 负责人:
  • 金额:
    $ 332.96万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-08-15 至 2025-07-31
  • 项目状态:
    未结题

项目摘要

ABSTRACT/SUMMARY The U.S. is experiencing a crisis of opioid misuse, addiction, and overdose; in the most recent year, there were over 100,000 drug-related overdose deaths, 75% of which involved opioids. Current pharmacotherapies for opioid use disorder (OUD) target mu opioid peptide (MOP) receptors, one of five classes of opioid receptors. These therapies include the full MOP agonist methadone, the partial MOP agonist buprenorphine, and the MOP antagonist naltrexone. There are several drawbacks in using these medications to treat OUD, which include the potential for abuse, development of physical dependence, and risk of overdose, particularly for methadone and buprenorphine. Buprenorphine and naltrexone also trigger severe withdrawal symptoms. There is thus an urgent need for an improved therapeutic for the treatment of OUD. Cebranopadol (TRN-228) is a first-in-class synthetic drug developed for its dual-action mechanism in treating pain, mediated by high affinity and potency for both MOP and nociceptin/orphanin FQ receptor (NOP). NOP receptor activation has been associated with reduced development of tolerance, abuse-related behavior, addiction, and physical dependence. In this UG3/UH3 proposal, Park Therapeutics is developing TRN-228 as a first-in-class dual MOP/NOP agonist that can be used as a safe and effective treatment for OUD. Preliminary nonclinical and clinical data indicate that cebranopadol has low potential for abuse and physical dependence and produces milder respiratory depression compared to pure MOP agonists such as morphine and oxycodone. TRN-228 also decreases morphine, heroin, and cocaine self-administration in rats and did not induce withdrawal when given to opioid-dependent rats. The UG3 phase of this proposal will test whether oral TRN-228 is a safe and potentially effective alternative treatment for OUD, based on the following Specific Aims: 1) determining the effects of TRN-228 on intravenous fentanyl self-administration and fentanyl-induced respiratory depression in opioid-dependent rats, 2) determining the IV abuse potential of TRN-228, and 3) assessing the ability of TRN-228 to suppress withdrawal. Upon meeting the UG3 Go/No-Go milestones, Park will progress to the UH3 phase which will demonstrate the therapeutic efficacy of TRN-228 in decreasing opioid use with low risk of withdrawal or abuse, which will be accomplished by 4) determining the effects of TRN-228 on fentanyl-induced respiratory depression in opioid-tolerant participants and 5) evaluating the ability of TRN-228 to block the subjective effects of hydromorphone. These studies will significantly advance the field by establishing the safety and preliminary efficacy of TRN-228. Successful completion of these aims will guide future efforts to establish a clinical program for FDA approval.
摘要/总结 美国正在经历阿片类药物滥用、成瘾和过量的危机;在最近的一年里,有 超过 100,000 人因吸毒过量死亡,其中 75% 涉及阿片类药物。目前的药物治疗 阿片类药物使用障碍 (OUD) 靶向 mu 阿片肽 (MOP) 受体,这是五类阿片受体之一。 这些疗法包括完全 MOP 激动剂美沙酮、部分 MOP 激动剂丁丙诺啡和 MOP 拮抗剂纳曲酮。使用这些药物治疗 OUD 有几个缺点,其中包括 滥用的可能性、身体依赖性的发展以及过量的风险,特别是美沙酮和 丁丙诺啡。丁丙诺啡和纳曲酮也会引发严重的戒断症状。因此有一个紧迫的任务 需要改进的 OUD 治疗方法。 Cebranopadol (TRN-228) 是一种一流的合成药物 因其治疗疼痛的双重作用机制而开发的药物,通过对两者的高亲和力和效力介导 MOP 和伤害感受肽/孤啡肽 FQ 受体 (NOP)。 NOP 受体激活与减少 耐受性、虐待相关行为、成瘾和身体依赖性的发展。在这个UG3/UH3 根据提案,Park Therapeutics 正在开发 TRN-228 作为一流的双 MOP/NOP 激动剂,可以 被用作 OUD 的安全有效的治疗方法。初步非临床和临床数据表明 头孢拉多滥用和身体依赖性的可能性较低,并产生较轻微的呼吸抑制 与吗啡和羟考酮等纯 MOP 激动剂相比。 TRN-228 还可以减少吗啡、海洛因、 大鼠自行给药可卡因,并且给予阿片类药物依赖大鼠时不会诱导戒断。这 该提案的 UG3 阶段将测试口服 TRN-228 是否是一种安全且可能有效的替代疗法 对于 OUD,基于以下具体目标:1) 确定 TRN-228 对静脉注射芬太尼的影响 阿片类药物依赖大鼠的自我给药和芬太尼诱导的呼吸抑制,2) 确定 IV TRN-228 的滥用潜力,以及 3) 评估 TRN-228 抑制戒断的能力。见面后 UG3 Go/No-Go 里程碑,Park 将进入 UH3 阶段,这将证明治疗效果 TRN-228 减少阿片类药物使用且戒断或滥用风险较低,这将通过 4) 完成 确定 TRN-228 对阿片类药物耐受参与者中芬太尼诱导的呼吸抑制的影响,以及 5)评估TRN-228阻断氢吗啡酮主观效应的能力。这些研究将 通过确定 TRN-228 的安全性和初步功效,显着推进了该领域的发展。成功的 这些目标的完成将指导未来建立 FDA 批准的临床计划的努力。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Mark K Greenwald其他文献

Mark K Greenwald的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Mark K Greenwald', 18)}}的其他基金

Planning a Multi-Level Intervention to Reduce Substance Use Stigma in HIV Prevention and Care
规划多层次干预措施以减少艾滋病毒预防和护理中的药物使用耻辱
  • 批准号:
    10669764
  • 财政年份:
    2021
  • 资助金额:
    $ 332.96万
  • 项目类别:
Behavioral Economic Analysis of Medical Marijuana Use in HIV+ Patients
HIV 患者使用医用大麻的行为经济学分析
  • 批准号:
    8331559
  • 财政年份:
    2011
  • 资助金额:
    $ 332.96万
  • 项目类别:
Behavioral Economic Analysis of Medical Marijuana Use in HIV+ Patients
HIV 患者使用医用大麻的行为经济学分析
  • 批准号:
    8484810
  • 财政年份:
    2011
  • 资助金额:
    $ 332.96万
  • 项目类别:
Behavioral Economic Analysis of Medical Marijuana Use in HIV+ Patients
HIV 患者使用医用大麻的行为经济学分析
  • 批准号:
    8228758
  • 财政年份:
    2011
  • 资助金额:
    $ 332.96万
  • 项目类别:
Human Laboratory Model of Cocaine Treatment: Behavioral Economic Analysis
可卡因治疗的人体实验室模型:行为经济学分析
  • 批准号:
    7894996
  • 财政年份:
    2009
  • 资助金额:
    $ 332.96万
  • 项目类别:
Human Laboratory Model of Cocaine Treatment: Behavioral Economic Analysis
可卡因治疗的人体实验室模型:行为经济学分析
  • 批准号:
    7697838
  • 财政年份:
    2009
  • 资助金额:
    $ 332.96万
  • 项目类别:
Development and Use of rtfMRI for Self-control of Nicotine Craving
rtfMRI 的开发和使用用于自我控制尼古丁渴望
  • 批准号:
    7588461
  • 财政年份:
    2008
  • 资助金额:
    $ 332.96万
  • 项目类别:
Development and Use of rtfMRI for Self-control of Nicotine Craving
rtfMRI 的开发和使用用于自我控制尼古丁渴望
  • 批准号:
    8087596
  • 财政年份:
    2008
  • 资助金额:
    $ 332.96万
  • 项目类别:
Development and Use of rtfMRI for Self-control of Nicotine Craving
rtfMRI 的开发和使用用于自我控制尼古丁渴望
  • 批准号:
    8104244
  • 财政年份:
    2008
  • 资助金额:
    $ 332.96万
  • 项目类别:
Development and Use of rtfMRI for Self-control of Nicotine Craving
rtfMRI 的开发和使用用于自我控制尼古丁渴望
  • 批准号:
    8282904
  • 财政年份:
    2008
  • 资助金额:
    $ 332.96万
  • 项目类别:

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    $ 332.96万
  • 项目类别:
    Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    $ 332.96万
  • 项目类别:
    Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    $ 332.96万
  • 项目类别:
    Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 332.96万
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    $ 332.96万
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    $ 332.96万
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 332.96万
  • 项目类别:
    EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    $ 332.96万
  • 项目类别:
    Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 332.96万
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    $ 332.96万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了